TW202415661A - Crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan -2-yl)-1h,2h,3h,4h,5h-[1,4]diazepino[1,7-a]indol-9-yl]-1,2- dihydropyridin-2-one and salts thereof, method of preparation, and uses thereof - Google Patents

Abstract

The present disclosure relates to hydrochloride salts of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), a potent, and orally active selective melanin-concentrating hormone receptor 1 (MCHR1) antagonist useful in the treatment and/or prevention of obesity, obesity related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addictive disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic conditions of the musculo-skeletal system, osteoporosis, cancer, and also in Prader-Willi Syndrome (PWS) or in one or more symptoms of PWS. The present disclosure also relates to crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form, different crystalline forms of the hydrochloride salt thereof, methods of producing the same, pharmaceutical compositions thereof, and therapeutic applications thereof as well.

Description

Crystal form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one and its salt, preparation method, and use thereof

The present disclosure relates to the hydrochloride of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is useful for treating and/or preventing obesity, obesity-related comorbidities and complications, diabetes, metabolic disorders, coronary artery disease, A potent, orally active, selective melanin concentrating hormone receptor 1 (MCHR1) antagonist for cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form, different crystalline forms of its hydrochloride salt, methods for making the same, pharmaceutical compositions thereof, and therapeutic applications thereof.

MCHR1 antagonists, including 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (described below, hereinafter referred to as Compound 1) in free base form, and maleic acid salts thereof are proposed in WO 2016/166684 A1.

Melanin-concentrating hormone (MCH) plays multiple roles in energy homeostasis and is central to the control of food intake and energy expenditure in the hypothalamus (Pissios et al., Endocr Rev 2006, 27(6):606-620). MCH has attracted much attention due to its effects on food intake and body weight, and its receptor MCHR1 remains one of the viable targets for obesity treatment (Pissios P., Peptides 2009, 30(11):2040-2044). MCH is one of the most potent central stimulants of feeding, regulating energy balance and mood (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Pissios et al., Endocr Rev 2006, 27(6):606-620; Forray C., Curr Opin Pharmacol 2003, 3: 85-89; Qu et al., Nature 1996, 380: 243-47; Hervieu G., Expert Opin Ther Targets 2003, 7: 495-511; Chung et al., J Mol Neurosci 2011, 43:115-21). Prader-Willi syndrome (PWS) is a rare, complex neurodevelopmental genetic disorder caused by the absence of imprinted gene expression in the paternally derived region of chromosome 15q11.2-q13. PWS is the most common syndromic cause of life-threatening obesity, with an estimated prevalence of 1/10,000 to 1/25,000 live births, occurring equally in both males and females, and across ethnicities. The syndromic obesity caused by severe overeating is derived from the neurodevelopmental consequences of the small nucleolar C/D box RNA 116 (SNORD116) cluster deletion (which has been shown to be the smallest deleted region) that is always involved in cases of paternal copy deletion (Holm et al., Pediatrics 1993, 91:398-402; Gunay-Aygun et al., Pediatrics 2001, 108:E95; Duker et al., Eur. J. Hum. Genet. 2010;18:1196-201; de Smith et al., Hum. Mol. Genet. 2009, 18:3257-65; Bieth et al., Eur. J. Human Genet. 2015, 23:252-255; Polex-Wolf et al., J. Clin. Invest . 2018, 128:960-969; Tan et al., Genes 2020, 11:128; Chung et al., Open Biology 2020, 10:200195). Bulimia, a key behavioral symptom in PWS, has significant impacts on patient and caregiver well-being that go beyond weight gain alone. Management of binge eating is ranked as the highest priority among caregivers for PWS treatment goals. The uncontrolled appetite, weight gain, and impaired reproductive capacity of PWS may be explained by overactive MCH neurons due to a loss of "checks and balances" caused by a decrease in the amount of ORX in the lateral hypothalamus. Preventing MCH overactivity is most likely to improve MCH-ORX balance, which can ultimately help patients reduce symptoms related to eating. According to the latest preclinical reports, the MCH-MCHR1 system is overactive due to impaired ORX control, and PWS patients can benefit from MCHR1 antagonist treatment to control overeating and obesity (Pace M., JCI Insight 2020, 5:e137495; Pace et al., Hum. Mol. Genet. 2020, 29:2051-2064; Linehan et al., Mol. Meatabolism 2020, 36:100977; Linehan et al., J. Physiol 2022, 596:305-316). Therefore, MCHR1 antagonists may be used to treat diseases or conditions associated with melanin-concentrating hormone receptor 1 activity, such as obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, cancer, as well as for PWS or for one or more symptoms of PWS.

For the purpose of pharmaceutical formulation and administration to patients, it is necessary to provide Compound 1 in a suitable form. However, the solid form of Compound 1 and its pharmaceutically acceptable salts, such as crystalline form, co-crystal or pseudo-polymorph/solvatomorph, is not shown in the prior art.

Polymorphism is the ability of a compound to exhibit two or more different crystalline phases with different arrangements of the molecules in the crystal lattice (J. Bernstein (2002) Polymorphism in molecular Crystals, Oxford Univ. Press. p. 2-4). Although polymorphs have the same chemical composition, their packing and geometric arrangements are different and they exhibit different physical properties, such as melting point, X-ray diffraction pattern, crystal habit, density, stability, solubility, mechanical properties (such as hardness, compactibility, tableting properties, flow, mixing), rheological parameters, etc.

Extensive research is conducted in the pharmaceutical industry to develop different polymorphs of various drug substances (R. Hilfiker (ed. 2006) Polymorphism in the Pharmaceutical Industry, Wiley-VCH, p. 1-15) in order to obtain suitable polymorphs or pseudopolymorphs with improved performance characteristics. A general requirement for the active ingredient in the development of pharmaceutical compositions is that the active ingredient has appropriate physical, physicochemical and chemical parameters. Examples of such parameters include solubility, especially aqueous solubility. Another important characteristic to be considered in industrial-scale production is ease of handling and good isolation properties, which are extremely important for the economic efficiency of the process. Another important aspect is that the solid form of the active ingredient has appropriate physical and chemical stability, for example, it does not absorb moisture and does not deteriorate significantly. Furthermore, different polymorphic forms of a given salt may have different solid phase characteristics, physical and chemical stabilities. To date, there is no real number of different solid forms in which a given compound may exist that can be used to clearly predict a given new chemical entity. This also applies to predicting all the complex physical and chemical properties that need to be considered in pharmaceutical development for a given form. Therefore, exploring the polymorphic morphology of compounds and discovering and making solid forms that exist in reality remain experimental challenges and important areas of invention in the pharmaceutical field. There is a great need to find new solid forms of compounds with favorable pharmaceutical properties.

Pseudopolymorphism is the ability of a compound to coexist in two or more different crystalline phases with different solvents. It is generally recommended not to use solvents that can form solvates with a particular compound during the crystallization process to make that compound (Hilfiker et al. (2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; p. 245-246; Wiley-VCH). In addition, with the exception of hydrates used in pharmaceutical development, the use of solvate forms is highly unfavorable because trace amounts of organic solvents can be harmful (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier). Furthermore, solvate forms are known to display variable composition, which may raise reproducibility and long-term stability issues.

International patent application WO 2016/166684 provides a method for preparing the maleic acid salt of compound 1. The reproduction experiment of Example 20(b) of WO 2016/166684 confirmed that the isolated crystalline solid was an ethanol solvent compound, which was not suitable for pharmaceutical development.

Other experiments confirmed that the maleic acid salt of compound 1 showed an increased tendency to form solvent complex forms, exhibiting various pseudopolymorphs in different organic solvents such as methanol, ethanol, dichloromethane, dimethyl sulfoxide, etc. The common feature of these solvent complex forms is an increase in solvent content (greater than 1% by thermogravimetric analysis (TGA)). The increased tendency to form new polymorphs, especially solvent complexes, indicates the risk of polymorph transformation or composition change during storage or pharmaceutical formulation. Therefore, it is not favorable to use the maleic acid salt of compound 1 in pharmaceutical products. Therefore, it is necessary to provide an improved form of compound 1 suitable for pharmaceutical formulation and for administration to humans.

International patent application WO 2016/166684 also provides for the isolation of compound 1 as a free base. Reproduction experiments confirmed that the product of Example 20(a) in WO 2016/166684 is a crystalline form with unfavorable stability properties, that is, it is a mesogenic crystalline form (Form B) of the base that is not suitable for pharmaceutical development. Form B of compound 1 tends to undergo polymorphic transformations when in contact with most solvents and when exposed to heat. Therefore, the use of compound 1 Form B in pharmaceutical products is unfavorable and does not meet the needs of a suitable solid form of compound 1 for pharmaceutical formulation and for treatment that effectively inhibits MCHR1 and is tolerable to patients.

Apart from the unfavorable maleate and base forms, no other solid forms of Compound 1 have been described in the prior art.

Therefore, there is a need to discover new solid forms of Compound 1 or pharmaceutically acceptable salts thereof that are suitable for pharmaceutical development and for administration to patients in need of treatment for diseases or conditions associated with melanin concentrating hormone receptor 1 activity and that are tolerated by such patients.

The present disclosure relates to the hydrochloride of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is useful for treating and/or preventing obesity, obesity-related comorbidities and complications, diabetes, metabolic disorders, coronary artery disease, Cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to a stable crystalline form of Compound 1 in free base form, to a stable crystalline form of its hydrochloride salt, a method for making the same in solid form, its pharmaceutical composition, and its therapeutic use.

As outlined above, it was found that the maleate salt of Compound 1 is not suitable for pharmaceutical formulation and for the treatment of MCHR1 that is effective and tolerable to patients.

International patent application WO 2016/166684 provides a method for preparing the maleic acid salt of compound 1 (reference example 1). The sample was found to be crystalline by XRPD (Figure 1), but a significant weight loss of 3.9% was detected by TGA. The reproduction experiment of Example 20 (b) of WO 2016/166684 - reference example 2 - confirmed that the isolated crystalline solid was an ethanol solvent compound (TGA: 5.1%).

With the exception of hydrates used in drug development, the use of solvate forms is highly unfavorable because trace amounts of solvent can be harmful (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier). Furthermore, solvate forms are known to exhibit variable composition, which may raise reproducibility and long-term stability issues. Therefore, solvates are generally not suitable for drug development, and it is generally recommended not to use solvents that can form solvates with a particular compound during the crystallization procedure to manufacture that compound (Hilfiker et al. (2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; p. 245-246; Wiley-VCH).

Other experiments were conducted to find suitable polymorphs of the maleate salt of Compound 1 for pharmaceutical development. Recrystallization experiments from various solvents (e.g., methanol, ethanol, dichloromethane, dimethyl sulfoxide) and by various crystallization methods (e.g., suspension stirring, cooling, evaporation) were designed and conducted to identify stable and solvent-free polymorphs of the maleate salt of Compound 1 (Reference Examples 2-9). In these experiments, several crystalline forms were identified (Figures 1-9) but the residual solvent content (determined by TGA) in all these experiments was above the acceptable limit, indicating that they were solvent complexes (Figures 10-17). The large amount of new pseudopolymorphs combined with the high residual solvent content (higher than 1% by TGA) indicates a risk of polymorph conversion or composition changes during storage or pharmaceutical formulation. Therefore, the use of the maleate salt of compound 1 in pharmaceutical products is disadvantageous and a need for a different more stable solid form arises.

As summarized above, the present invention relates to a stable crystalline free base and crystalline hydrochloride salt of Compound 1 that is acceptable for pharmaceutical development. The invention also relates to methods for identifying and preparing the crystalline form.

Crystalline solid phases can be identified by X-ray diffraction: the powder X-ray diffraction pattern or the position of one or more diffraction peaks is characteristic of crystalline materials. Alternatively, vibrational spectroscopy, such as IR and Raman spectroscopy, is also a suitable and widely used method for distinguishing different polymorphs/pseudopolymorphs/amorphous forms. Although vibrational spectroscopy mainly detects local, short-range order (intramolecular vibrations), the vibrational frequencies are also affected by their surroundings, making them indicative not only of the configurational polymorphism, but also of the way the molecules are stacked. Therefore, different polymorphs usually have different vibrational spectra if measured with sufficiently high wavenumber resolution (Hilfiker et al. (2019), p. 418). Therefore, each crystalline form of the free base and hydrochloride of Compound 1 of the present invention can be identified and distinguished from other crystalline forms by one or more of the following solid state analysis characteristics: characteristic XRPD diffraction peaks, IR absorption bands or Raman peaks.

One aspect of the present invention is a hydrochloride of compound 1. The salt can exist in various forms such as oil or solid. The solid can be amorphous, crystalline or a mixture of the two.

In another embodiment, the present invention provides a method for preparing Compound 1 hydrochloride, which comprises: a) providing a solution of Compound 1 in any suitable solvent; b) mixing the solution in step a) with a hydrochloric acid solution; c) stirring the slurry; and d) isolating Compound 1 hydrochloride.

The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

The solvent used in step b) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

Step c) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

Another aspect of the present invention is a stable anhydrate form of the hydrochloride salt of Compound 1, Form A.

Another aspect of the invention is a hydrochloride salt of Compound 1 comprising at least 5%, at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, at least 95%, at least 99% of Compound 1 Hydrochloride Form A.

The X-ray diffraction pattern of Compound 1 hydrochloride Form A is shown in Figure 18. The detailed peak list is shown in Table 1. The most characteristic peaks of Compound 1 hydrochloride Form A are at 9.2, 12.5, 14.5, 15.1, 15.8, 17.4±0.2° 2θ.

Compound 1 hydrochloride Form A can also be characterized by its FT-IR spectrum. The infrared spectrum of Compound 1 hydrochloride Form A is shown in Figure 19. A detailed list of the absorption bands of Compound 1 hydrochloride Form A is shown in Table 2. The most characteristic absorption bands of Compound 1 hydrochloride Form A are at 2474, 2524, 1668, 1479 and 1222±4 cm ^-1 .

Compound 1 hydrochloride Form A can also be characterized by its Raman spectrum. The Raman spectrum of Compound 1 hydrochloride Form A is shown in Figure 20. A detailed list of Raman peaks of Compound 1 hydrochloride Form A is shown in Table 3. The most characteristic Raman peaks of Compound 1 hydrochloride Form A are at 1549, 1344, 1303, 1257 and 747 cm ^-1 .

Compound 1 hydrochloride Form A can also be characterized by its differential scanning calorimetry (DSC) thermogram. A typical DSC thermogram of Compound 1 hydrochloride Form A is shown in Figure 21. Compound 1 hydrochloride Form A melts during decomposition with a broad endothermic DSC peak with a peak maximum between 250 and 300 °C.

Compound 1 hydrochloride Form A was confirmed to be a true anhydrate form by its thermogravimetric (TGA) thermogram as shown in Figure 22. The weight loss of Compound 1 hydrochloride Form A was less than 1.0% (up to 175°C).

The chemical stability of Compound 1 hydrochloride Form A was evaluated by a set of forced stability studies as shown in Table 4. Samples of Compound 1 hydrochloride Form A were stored under different controlled conditions (50°C dry, 75°C dry, and 50°C 85% RH) for 10 days and analyzed in the same manner as the initial samples.

The impurity profile, loss on drying, and polymorphic form of samples of Compound 1 hydrochloride Form A did not change during the forced stability study, demonstrating that Compound 1 hydrochloride Form A is stable at 50°C, 75°C, and at 50°C 85% RH for up to 10 days.

The term solubility is used to measure the amount of compound 1 hydrochloride (in μmol) that can be dissolved in 1 L of simulated solvent. Simulated solvents include FaSSiF (fasted state simulated intestinal fluid) and FeSSiF (fed state simulated intestinal fluid). A drug substance is considered highly soluble according to the Biopharmaceutics Classification System (BCS) when the highest concentration is soluble in 250 mL or less of aqueous medium in the pH range of 1-6.8 at 37±1°C (Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Guidance for Industry, December 2017, https://www.gmp-compliance.org).

The solubility data of Compound 1 HCl Form A in FaSSiF and FeSSiF solutions are shown in Table 5. In the simulated fluids (FaSSiF and FeSSiF), Compound 1 HCl Form A is highly soluble up to a concentration of 20 mg.

The above analysis and physical characterization analysis confirmed that Compound 1 hydrochloride Form A is a stable anhydrous polymorph of Compound 1 hydrochloride that is highly soluble in the simulated medium. It is not hygroscopic under normal conditions (up to 70% RH), but requires some protective measures under high humidity. The analytical results indicate that the solid form is suitable for pharmaceutical development.

In another embodiment, the present invention provides a method for preparing Compound 1 hydrochloride Form A, which comprises: a) providing a solution of Compound 1 hydrochloride in any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; and c) stirring the slurry; and d) isolating Compound 1 hydrochloride Form A.

The solution provided in step a) can be provided by dissolving Compound 1 hydrochloride or by mixing Compound 1 and an appropriate amount of hydrochloric acid in a solution.

The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

Step b) involves evaporating the solvent by any suitable technique, including a rotary distillation apparatus such as a rotary evaporator, an open reactor or any other suitable technique. Evaporation can be induced by increasing the temperature or by reducing the pressure or a combination thereof.

Step c) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

In another embodiment, the present invention provides a method for preparing Compound 1 hydrochloride Form A, comprising: a) providing a solution of Compound 1 hydrochloride in any suitable solvent; b) cooling the solution to obtain a slurry; and c) stirring the slurry; and d) isolating Compound 1 hydrochloride Form A.

The solution provided in step a) can be provided by dissolving Compound 1 hydrochloride or by mixing Compound 1 and an appropriate amount of hydrochloric acid in a solution.

The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.

Step b) involves cooling the solution to a temperature lower than that of step a), for example to room temperature or 0-5°C or any suitable temperature.

Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

In another embodiment, the present invention provides a method for preparing Compound 1 hydrochloride Form A, comprising: a) providing a solution of Compound 1 hydrochloride in any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) agitating the slurry; and d) isolating Compound 1 hydrochloride Form A.

The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.

Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.

Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

International patent application WO 2016/166684 also provides for the isolation of compound 1 as a free base. Reference Example 10 demonstrates that the evaporation of the solvent as described in Example 20(a) of WO 2016/166684 produces a crystalline form of compound 1 free base, Form B. Analytical characterization of Compound 1 Form B, in particular DSC analysis, revealed that this form undergoes polymorphic transitions at higher temperatures and forms a new form with a melting point between 200 and 210° C. These DSC results indicate that Compound 1 free base Form B may not be a stable polymorph of Compound 1 free base.

According to Ostwald's rule of stages (Ostwald, 1897), in crystallization, the system moves from an initial high-energy state to equilibrium with minimal change in free energy, thus suggesting that the least stable polymorph can be isolated first in any crystallization (Jonathan C. Burley, Melinda J. Duer, Robin S. Stein, Ranko M. Vrcelj, European Journal of Pharmaceutical Sciences, Volume 31, Issue 5, August 2007, Pages 271-276). In order to obtain more stable polymorphs, further crystallization experiments (e.g., Example 3) were designed and performed using a more controlled crystallization procedure: an additional resuspension step was applied instead of rapid evaporation of the solvent. In Example 3, a new polymorphic form A of the free base of compound 1 with some trace amounts of form B was obtained. In further crystallization experiments, pure Form A was prepared and characterized.

Another aspect of the present invention is the stable anhydrate form of the free base of Compound 1, Form A.

Another aspect of the invention is a crystalline solid form of Compound 1 free base comprising at least 5%, at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, at least 95%, at least 99% of Compound 1 free base Form A.

The X-ray diffraction pattern of Compound 1 free base Form A is shown in Figure 23. The detailed peak list is shown in Table 6. The most characteristic peaks of Compound 1 free base Form A are at 5.9, 17.7, 18.1, 19.8 and 22.2° 2θ.

Compound 1 free alkali form A can also be characterized by its FT-IR spectrum. The infrared spectrum of compound 1 free alkali form A is shown in Figure 24. A detailed list of the absorption bands of compound 1 free alkali form A is shown in Table 7. The most characteristic absorption bands of compound 1 free alkali form A are at 1663, 1478, 1220, 860, 795 and 766±4 cm ^-1 .

Compound 1 alkali form A can also be characterized by its Raman spectrum. The Raman spectrum of Compound 1 alkali form A is shown in Figure 25. A detailed list of Raman peaks of Compound 1 alkali form A is shown in Table 8. The most characteristic Raman peaks of Compound 1 alkali form A are at 1554, 1345, 1267, 1260 and 750±4 cm ^-1 .

Compound 1 free base Form A can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 free base Form A is shown in Figure 26. Compound 1 free base Form A exhibits a single melting endotherm with an onset temperature value between 200 and 210 °C.

Compound 1 free base Form A was confirmed to be a true anhydrate form by its TGA thermogram shown in Figure 27. The weight loss of Compound 1 free base Form A was less than 0.5% (up to 215°C).

The chemical stability of Compound 1 free base Form A was evaluated by a set of forced stability studies as shown in Table 9. Samples of Compound 1 free base Form A were stored under different controlled conditions (50°C dry, 75°C dry, and 50°C 85% RH) for 10 days and analyzed in the same manner as the initial samples.

The impurity profile, loss on drying, and polymorphic forms of samples of Compound 1 free base Form A did not change during the forced stability study, demonstrating that Compound 1 hydrochloride Form A is stable at 50°C, 75°C, and at 50°C 85% RH for up to 10 days.

The solubility of Compound 1 free base Form A in PBS, FaSSiF and FeSSiF solutions is shown in Table 10. Compound 1 HCl Form A is highly soluble up to a concentration of 9 mg, but the solubility is higher in more acidic media.

The above analysis and physical characterization analysis confirmed that Compound 1 free base Form A is a stable, non-hygroscopic anhydrous polymorph of Compound 1 free base, which exhibits acceptable solubility in simulated media. The analytical results indicate that the solid form is suitable for pharmaceutical development.

In another embodiment, the present invention provides a method for preparing Compound 1 free base Form A, which comprises: a) providing a solution of Compound 1 free base in any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; and c) stirring the slurry; and d) isolating Compound 1 free base Form A.

The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

Step b) involves evaporating the solvent by any suitable technique, including a rotary distillation apparatus such as a rotary evaporator, an open reactor or any other suitable technique. Evaporation can be induced by increasing the temperature or by reducing the pressure or a combination thereof.

Step c) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

In another embodiment, the present invention provides a method for preparing Compound 1 free base Form A, comprising: a) providing a solution of Compound 1 free base in any suitable solvent; b) cooling the solution to obtain a slurry; and c) stirring the slurry; and d) isolating Compound 1 free base Form A.

The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.

Step b) involves cooling the solution to a temperature lower than that of step a), for example to room temperature or 0-5°C or any suitable temperature.

Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

In another embodiment, the present invention provides a method for preparing Compound 1 free base Form A, which comprises: a) providing a suspension of a solid form of Compound 1 free base in any suitable solvent; b) stirring the slurry; and c) isolating Compound 1 Form A.

In step a), the solid form of the free base of compound 1 may be form B or form D or form A or any mixture thereof. The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

Step b) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

In another embodiment, the present invention provides a method for preparing Compound 1 free base Form A, which comprises: a) providing a solution of Compound 1 free base in any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) stirring the slurry; and d) isolating Compound 1 free base Form A.

The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.

Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.

Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

In another embodiment, the present invention provides a method for preparing Compound 1 free base Form B, which comprises: a) providing a solution of Compound 1 free base in any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and d) isolating Compound 1 Form A.

The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.

The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.

Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

The X-ray diffraction pattern of Compound 1 Form B is shown in Figure 28. The detailed peak list is shown in Table 11. The most characteristic peaks of Compound 1 Form B are at 6.1, 16.0, 18.0, 19.2 and 21.5 ± 0.2° 2θ.

Compound 1 Form B can also be characterized by its FT-IR spectrum. The infrared spectrum of Form B is shown in Figure 29. A detailed list of the absorption bands of Compound 1 Form B is shown in Table 12.

Compound 1 Form B can also be characterized by its Raman spectrum. The Raman spectrum of Compound 1 Form B is shown in Figure 30. A detailed list of Raman peaks of Compound 1 Form B is shown in Table 13.

Compound 1 Form B can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 Form B is shown in Figure 31. Compound 1 Form B exhibits a broad exotherm between 100 and 200 °C prior to a melting endotherm that begins between 200 and 210 °C.

In another aspect, the present invention provides a method for preparing a pyridine solvent complex of Compound 1 free base Form C, which is prepared by suspending Compound 1 maleate in pyridine, stirring, and isolating a white or off-white solid Compound 1 free base Form C. Agitation involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C, or any other suitable temperature, by any suitable technique, including a stirring rod, a stirring rod, or a shaker.

The X-ray diffraction pattern of Compound 1 free base Form C is shown in Figure 32. The detailed peak list is shown in Table 14. The most characteristic peaks of Compound 1 free base Form C are at 2.6, 5.3, 16.0, 19.4 and 24.7±0.2° 2θ.

Compound 1 free base Form C can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 free base Form C is shown in Figure 33. Compound 1 free base Form C exhibits a broad endotherm between 50 and 150 °C prior to a melting endotherm starting between 200 and 210 °C.

A typical TGA thermogram of Compound 1 free base Form C is shown in Figure 34. The weight loss of Form C is about 10% to 120°C.

Another aspect of the present invention is the free base hydrate form of Compound 1, Form D.

Another aspect of the invention is a crystalline solid form of Compound 1 free base comprising at least 5%, at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, at least 95%, at least 99% of Compound 1 free base Form D.

The X-ray diffraction pattern of Compound 1 free base Form D is shown in Figure 35. The detailed peak list is shown in Table 15. The most characteristic peaks of Compound 1 free base Form D are at 8.1, 18.4, 18.8, 19.0 and 20.4 ± 0.2° 2θ.

Compound 1 free base Form D can also be characterized by its FT-IR spectrum. The infrared spectrum of Form D is shown in Figure 36. A detailed list of the absorption bands of Compound 1 free base Form D is shown in Table 15. The most characteristic absorption bands of Compound 1 free base Form D are at 3515, 3243, 2869, 2829 and 1650±4 cm ^-1 .

Compound 1 free base Form D can also be characterized by its Raman spectrum. The Raman spectrum of Form D is shown in Figure 37. A detailed list of Raman peaks of Compound 1 free base Form D is shown in Table 16. The most characteristic Raman peaks of Compound 1 free base Form D are at 1644, 1552, 1539, 1301, 1257±4 cm ^-1 .

Compound 1 free base Form D can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 free base Form D is shown in Figure 38. Compound 1 free base Form D exhibits a broad endotherm between 50 and 110 °C prior to a melting endotherm that begins between 200 and 210 °C.

Compound 1 free base Form D is a hydrated form, and its TGA thermogram shows a characteristic weight loss of 4.1% between 50 and 110°C. A typical TGA thermogram of Compound 1 free base Form D is shown in Figure 39. The water content of the sample was confirmed by Karl Fisher titration (4.6%).

In another embodiment, the present invention provides a method for preparing Compound 1 free base form D, which comprises: a) providing a solution of Compound 1 free base in any suitable solvent; b) mixing the solution with water to obtain a slurry; and c) stirring the slurry; and d) isolating Compound 1 free base form D.

The solvent used in step a) is selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, acetone, butanone, 2-pentanone, 3-pentanone, acetonitrile, tetrahydrofuran, 2-methoxyethanol, or a mixture thereof.

The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.

Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.

Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.

The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.

For the analytical studies the following experimental conditions were used: Parameters for FT-IR spectroscopy measurements: Instrument: Thermo-Nicolet 6700 Phase: KBr pellets Spectral resolution: 4 cm ^-1 Detector: DTGS Spectroscope: XT-KBr Mirror movement speed: 0.6329 Number of scans: 100 Parameters for FT-Raman spectroscopy measurements: Instrument: Thermo-Nicolet NXR9650 Measuring range: 3500 to 200 cm ^-1 Spectral resolution: 4 cm ^-1 Detector: Ge Spectroscope: CaF ₂ Mirror movement speed: 0.1581 Number of scans: 256 Laser performance: 500 mW Parameters for X-ray powder diffraction measurements: Instrument: PANanalytical X'Pert PRO MPD Radiation: CuKα Accelerating voltage: 40 kV Anode current: 40 mA Goniometer: PW3050/60 Scanning speed: 0.0305 s Increment: 0.0131° Sample holder: PW1818/25 & 40 (transmission, sample between foils) Sample holder rotator: PW3064/60 (reflection/transmission rotator) Sample holder rotation speed: 1 rev/sec Detector: PIXcel (PW3018/00) Uncertainty of 2θ measurement: ±0.2° Parameters for TGA measurement: Instrument: TA Instruments TGA Q5000 or Discovery TGA 5500 Heating rate: 10°C/min Sample weight: ~2 to 10 mg Atmosphere: 60 mL/min N ₂ DSC measurement parameters: Instrument: TA Instruments DSC Q1000 or Discovery DSC 2500 Heating rate: 10℃/min Sample weight: ~1 to 3 mg Pan type: Open Al pan Atmosphere: 50 mL/min N ₂ Solubility analysis method

About 2-2 mg (N=5) of the test substance was weighed in a transparent test container and 300 μL of the solvent was added thereto. The test container was placed on a mechanical shaker and shaken at 37°C for 24 h of incubation time, filtered and the concentration of compound 1 in the filtrate was determined by HPLC-MS (Agilent 1200 liquid chromatograph, coupled to 6410 QQQ-MS, Kinetex EVO C18 column). HPLC method for purity analysis

Weigh approximately 10-10 mg of the test substance in a 10 mL volume flask and dissolve in a mixture of formic acid, acetonitrile and water. Dilute 1 mL of the solution to 100 mL with the solvent mixture using a 100 mL volume flask. Then inject the diluted solution into a Waters Acquity H-Class UPLC instrument using an Acquity CSH column.

The physicochemical and biopharmaceutical properties of active substances are crucial in terms of in vivo and in vitro performance. Ideally, for oral solid dosage forms, crystalline compounds that are water-soluble, non-hygroscopic, stable and easy to process are preferred for development purposes. The physicochemical and formulation-related properties of the salts and crystalline forms of Compound 1 and its hydrochloride disclosed herein can be further characterized by the following methods:

Crystal habit: Crystalline polymorphic materials can exist in a number of shapes or forms (sometimes referred to as "crystal habits") depending on the method and solvent used for the final crystallization. This can range from high angle crystals with elongated, needle-like crystals and flat plate-like forms to more spherical crystal habits. The shape can affect the flowability of bulk powders, e.g., during discharge from a container/addition funnel, etc., due to particle-particle mechanical and physical interactions or cohesive forces. The shape of drug particles can be characterized, e.g., by polarizing light microscopy (PLM).

Particle size distribution: From the perspective of drug formulation, a narrow and monomodal particle size distribution of the active pharmaceutical ingredient is advantageous. Particle size distribution can be measured, for example, by laser diffraction and polarizing microscopy.

The specific surface area of the solid form can be determined by gas absorption (such as BET) or gas permeability method.

Dissolution: Solubility is important in selecting a salt form or a specific crystalline or polymorphic form which will affect the dissolution rate and is the most critical parameter. Dissolution is the process by which a substance forms a solution. Dissolution tests measure the extent and rate of solution formation from dosage forms such as tablets, capsules, ointments, etc. The dissolution of a drug is important for its bioavailability and therapeutic effectiveness. Dissolution and drug release are terms used interchangeably. Differences in solubility and dissolution rate between polymorphs can have a significant effect on the oral bioavailability (dissolution and absorption from the GI tract) of a drug.

Flowability: Although the two most common solid dosage forms, tablets and capsules, have their own unique requirements, there are similarities between them. They both require the correct weight of material to flow into a specific volume. Good flow properties are essential for the successful manufacture of both tablets and powder-filled hard gelatin capsules or sachets. The European Pharmacopoeia (Ph. Eur.) contains a test for the flowability of powders based on how the powder flows vertically out of a funnel. There are several different methods that can be used to determine the flow properties of powders, and there are many examples in the literature that illustrate the correlation between the test methods and the manufacturing properties of the formulation.

Bulk density is a fundamental parameter in pharmaceutical product and process development and solid dosage form manufacturing. It is used to determine the amount of powder that can be packed into a certain space, such as a blender or feed hopper on a tablet press or capsule filler. It can also be used to determine the amount of powder that can be packed into a capsule of a specific volume.

The tapped density or simply tapped density is the maximum bulk density of a powder (or blend of powders) that is achieved under the influence of a well-defined externally applied force. The minimum bulk volume is therefore dependent on many factors, including particle size distribution, true density, particle shape and cohesion due to surface forces including water. Therefore, the tapped density of a material can be used to predict its flow properties and its compressibility.

The term "diseases or conditions associated with MCHR1 activity" refers to obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, and cancer.

This article refers to the field of a parallel patent application entitled “ MCHR1 antagonist for treating Prader-Willi syndrome ” filed by the inventor of the present case, which discloses a method for treating Prader-Willi syndrome using a compound of formula (I) according to WO 2016/166684 A1, such as compound 1 in free form or in a pharmaceutically acceptable salt form such as its hydrochloride.

The term "pharmaceutical composition" refers to Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or a mixture of Compound 1 hydrochloride Form A and other chemical components such as pharmaceutically acceptable excipients such as diluents or carriers. Pharmaceutical compositions facilitate administration of the compound to a subject.

The term "excipient" is defined as a chemical compound that enhances the incorporation of a compound into cells or tissues.

The pharmaceutical composition of the present invention can be formulated in many ways, for example, in the form of tablets, capsules, powders, granules, suspensions, emulsions, solutions, syrups, aerosols (with solid or liquid carriers), soft or hard gelatin capsules, suppositories, and injections in sterile form. Preferably, the pharmaceutical composition is formulated in the form of tablets or capsules.

The pharmaceutical composition may be in a single dosage form containing a predetermined amount of active ingredient. The dosage form may contain a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A or a given percentage of a therapeutically effective amount, so that these single dosage forms for repeated administration can be administered at a given time to achieve the desired therapeutically effective dose. Preferred single dosage forms are those containing a daily dose or sub-dose or a given percentage of active ingredients as described above. In addition, these pharmaceutical compositions can be manufactured by methods known in the art.

The term "therapeutically effective amount" refers to the amount of active ingredient that results in the treatment, cure, prevention, alleviation or improvement of a disease, pathological condition, side effect, one or more symptoms of a disease (such as overeating) to maintain or reduce body weight or reduce food intake, or inhibit or delay the progression of a disease, pathological condition of a disease, or one or more symptoms (such as overeating) compared to an individual who has not received such amount. The term also includes an effective amount required to improve normal physiological function. In therapeutic applications, Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A can be administered in a therapeutically effective amount as an unformulated drug substance, or the active ingredient can be formulated into a drug. The exact therapeutically effective amount of the compound depends on several factors, including but not excluding the age and weight of the individual (patient), the type and severity of the disease to be treated, the type of pharmaceutical composition/drug and the route of administration.

The term "daily dose" means the amount of free base administered daily. In the case of administration of pharmaceutically acceptable salts, the daily dose is also expressed in free base equivalents.

In one embodiment, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A is a daily dose of at least about 2.5 mg.

In another embodiment, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A is a daily dose of about 2.5 mg to about 22.5 mg.

In a preferred embodiment, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, crystalline Compound 1 hydrochloride, or Compound 1 hydrochloride Form A is a daily dose of about 2.5 mg to about 7.5 mg.

In a particularly preferred embodiment, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, crystalline Compound 1 hydrochloride, or Compound 1 hydrochloride Form A is a daily dose of about 2.5 mg, about 5 mg, or about 7.5 mg.

The term "effective amount" refers to the amount of a drug or active ingredient sufficient to elicit the biological or medicinal response in a tissue, system, animal (including human) to which the drug is administered, for example.

The term "subject" refers to a patient requiring any of methods 1.1 to 1.7 as defined below.

Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A can be administered by any appropriate route, such as oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular, or intranasal. The preferred route of administration is oral.

In a series of additional specific or alternative embodiments, the present invention provides: 1.1. A method for treating a disease or condition associated with MCHR1 activity in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.2. A method for treating Prader-Willi syndrome in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.3. A method for improving, alleviating or delaying the progression of one or more symptoms of PWS in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.4. A method for maintaining the weight of a patient suffering from PWS in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.5. A method for reducing weight in an individual suffering from PWS in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.6. A method for reducing food intake in an individual suffering from PWS in need thereof, comprising administering to the individual a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.6. A method for treating binge eating disorder in a patient suffering from PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein. 1.7. A method as described above, wherein Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A is administered once daily. 2.   A pharmaceutical composition for use in any of methods 1.1 to 1.7, comprising Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein and one or more pharmaceutically acceptable excipients. 4.   Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein, for use in any of methods 1.1 to 1.7. 5.   Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in a crystalline form, or Compound 1 hydrochloride Form A as described herein, for use in the preparation of a medicament for use in any of methods 1.1 to 1.7. 6.   Use of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A as described herein for any of methods 1.1 to 1.7.

In particular, Compound 1 hydrochloride Form A as described herein can be used to treat binge eating in patients suffering from PWS.

Other details of the present invention are presented in the following examples, and the scope of protection of the present invention is not limited to the examples described in any aspect. Unless explicitly stated in individual examples, the starting materials of the following examples are prepared according to Example 20 (a) of WO 2016/166684 - Compound 1 free base, or prepared according to 20 (b) - Compound 1 maleic acid salt. Reference Examples

Reference Example 1 Compound 1 maleic acid salt solution from ethanol To a solution of 0.47 g (1.015 mmol) of Compound 1 (WO 2016/166684 Example 20/a) in a 10:1 mixture of dichloromethane and methanol, 0.13 g (1.117 mmol) of maleic acid was added, and the mixture was concentrated. The residue was titrated with ethanol, and the solid product was filtered after stirring for 1 h, washed with ethanol, and dried to obtain 0.57 g (96%) of the title compound. The XRPD pattern of the product is shown in Figure 1. TGA: 3.9% (Figure 10).

Reference Example 2 Compound 1 maleic acid salt solvent from ethanol 99.11 mg of compound 1 maleic acid salt was dissolved in 5 ml of ethanol (jacket temperature 70°C), filtered and the filtrate was cooled to 25°C, stirred for 30 min, filtered and left to dry at room temperature for 4 days. The XRPD pattern of the product is shown in Figure 2. TG: 5.1% (Figure 11)

Reference Example 3 Compound 1 maleic acid salt solvent from dichloromethane/ethanol 0.231 kg 4-[(5-chloropyridin-2-yl)methoxy]-1-{1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one (Example 4 in WO 2016/166684) was dissolved in 20 l acetonitrile, and 0.3 kg K ₂ CO ₃ and 520 ml 2-iodopropane were added and stirred at reflux for 10 h, and the product was isolated by evaporating the solvent (100 mbar, 40-45° C.). The crude product was dissolved in 1.1 L of dichloromethane and washed with 3×1 l of water, and the crude base was isolated by evaporation of the solvent (100 mbar, 40-45° C.). The solid was dissolved in 1.5 l of dichloromethane and a solution of 65 g of maleic acid in 3.6 l of ethanol was added thereto. The suspension was concentrated by evaporation of 3.1 l of solvent, 2 l of ethanol was added and a further 1.5 l was evaporated, the resulting suspension was stirred at 20-25° C. for one hour, cooled to 10-12° C., stirred for one hour, filtered, washed with 2×0.5 l of ethanol and dried at 75-80° C. for 7 hours to obtain 0.197 kg of a white solid. The XRPD pattern of the product is shown in FIG. 3 . TGA: 4.1% (Figure 12).

Reference Example 4 Compound 1 maleic acid salt solvent from methanol 40 mg of compound 1 maleic acid salt was suspended in 1 ml methanol, stirred for one week, filtered and dried under ambient conditions. The XRPD pattern of the product is shown in Figure 4. TGA: 5.5% (Figure 13).

Reference Example 5 Compound 1 maleic acid salt solvent from ethanol 40 mg of compound 1 maleic acid salt was suspended in 1 ml of ethanol, stirred for one week, filtered and analyzed by XRPD. The XRPD pattern of the product is shown in Figure 5. TGA: 4.7% (Figure 14)

Reference Example 6 Compound 1 maleic acid salt solvent from ethanol To a solution of 0.47 g (1.015 mmol) of compound 1 in 5 ml of a 10:1 mixture of dichloromethane and methanol, a solution of 0.13 g of maleic acid in 3.5 ml of the same solvent was added, and the mixture was evaporated by Rotavapor (500-350 mbar, 40°C). 1.9 ml of ethanol was added to the solid residue, stirred for one hour, filtered and left to dryness at room temperature. The XRPD pattern of the product is shown in Figure 6. TGA: 1,9% (Figure 15)

Reference Example 7 Solution of maleic acid salt of compound 1 from methanol 50 mg of maleic acid salt of compound 1 was dissolved in 1 ml of methanol, and the solvent was evaporated at room temperature. The XRPD pattern of the solid is shown in Figure 7. TGA: 4.3% (Figure 16).

Reference Example 8 Compound 1 maleic acid salt solvent from methanol 101 mg of compound 1 maleic acid salt was suspended in 2.5 ml methanol, stirred for one week, filtered and analyzed by XRPD. The XRPD pattern of the product is shown in Figure 8. The sample was dried at 40°C overnight. TGA: 2.7% (Figure 17).

Reference Example 9 Compound 1 maleate solution from DMSO 272 mg of compound 1 maleate was suspended in 0.75 ml DMSO and stirred at room temperature for one week. The solid was filtered and analyzed by XRPD. The XRPD pattern of the product is shown in Figure 9.

Reference Example 10 0.6 g of compound 1 was dissolved in 5 ml of a 95:5:0.1 mixture of dichloromethane, methanol and ammonia. The solvent was evaporated in a Rotavapor (40°C 500 mbar) to obtain 0.6 g of off-white powder. Yield: 100%. The XRPD of the product is shown in Figure 40. Example

Example 1 To a solution of 30 mg of the free base of compound 1 in 1.2 ml of acetone, 7.5 µl of 37% hydrochloric acid was added dropwise, stirred for 3 h, filtered and dried at 40°C/vacuum. Yield: N/A. The XRPD pattern of the product is according to Figure 18, and the water content measured by TGA is 0.6% (to 200°C).

Example 2 To a solution of 3 g of the free base of compound 1 in 36 ml of dichloromethane was added 0.6 ml of a solution of hydrochloric acid in 36 acetone. The resulting suspension was cooled to 0°C and stirred for 3 hours. The solid was filtered, washed with acetone and dried at 60°C to obtain 3.10 g of compound 1 hydrochloride. Yield: 96%. The XRPD pattern, FT-IR and FT-Raman spectra, DSC and TGA curves of the product are shown in Figures 18 to 22.

Example 3 5.23 g of crude Compound 1 free base was dissolved in a mixture of 30 ml of dichloromethane, 15 ml of ethanol and 15 ml of toluene and concentrated by evaporation. The product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent and a 95:5:0.1 mixture of dichloromethane, methanol and cc. NH ₃ solution as eluent. The eluent (Rotavapor) was removed and the product was resuspended in ethanol, dried, resuspended in diethyl ether and filtered to obtain 1.24 g of white crystals. The XRPD pattern of the product is shown in Figure 41, confirming that it is a mixture of Compound 1 Form B and Compound 1 Form A.

Example 4 100 mg of a mixture of Compound 1 free base, Form A and Form B was suspended in 2 ml of ethanol and stirred at room temperature for one week. The solid was filtered and identified as Compound 1 Form A by XRPD.

Example 5 96.76 mg of compound 1 was dissolved in 11 ml of ethanol under reflux, cooled and stirred for about 3 days to obtain a white precipitate identified as compound 1 free base form A. The XRPD pattern of the product is shown in Figure 23.

Example 6 83.5 mg of Compound 1 free base was dissolved in 15 ml of acetonitrile and stirred in an open vial for two days, and the solid was filtered to obtain a white to off-white precipitate identified as Compound 1 free base Form A. The XRPD pattern of the product is according to Figure 23.

Example 7 1.17 g of Compound 1 free base was dissolved in 13.2 ml of dichloromethane and 2 ml of the solution was added to 2 ml of tetrahydrofuran and stirred overnight to obtain a white precipitate identified as Compound 1 free base Form A. The XRPD pattern of the product is shown in Figure 23.

Example 8 1.17 g of compound 1 free base was dissolved in 13.2 ml of dichloromethane and 2 ml of the solution was added to 2 ml of methyl tert-butyl ether to obtain a white precipitate identified as compound 1 free base form B. The XRPD pattern of the product is according to Figure 28.

Example 9 51.20 mg of Compound 1 maleic acid salt was suspended in 1.5 ml pyridine and stirred for one week. The solid was filtered and dried in vacuum at 40°C to obtain Compound 1 free base Form C. The XRPD pattern of the sample is shown in Figure 36, TGA: 10.3% (Figure 34). NMR: Compound 1, confirmed with 0.4 mol pyridine and 0.15 mol maleic acid. Melting of Form A was detected on DSC (Figure 33).

Example 10 131.5 g of compound 1 free base was dissolved in 18.5 ml of dichloromethane and 1.2 ml of the solution was added to 1 ml of n-hexane mixed with 17 µl cc. HCl. The solid was filtered and dried at 40°C. The XRPD pattern of the sample was confirmed to be compound 1 form D according to Figure 35. TGA: 4.1% (215°C).

Example 11 A solution of 1 g of compound 1 free base in 50 ml of tetrahydrofuran was added to 150 ml of water under reflux, stirred for one hour, and filtered and washed with water. The XRPD pattern of the sample is shown in Figure 35. Preparation of pharmaceutical composition

The following formulation examples illustrate individual pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical compositions. A) Solid oral dosage form Tablets or capsules or filled packets Active substances 0.005-90% filler 0.1-99.9% Adhesive 0-20% Disintegrating Agents 0-20% Lubricant 0-10% Glidants 0-10% Other specific formulations 0-50% B) Parenteral Intravenous injection Active substances 0.001-50% Solvent 10-99.9% Co-solvent 0-99.9% Osmotic agents 0-50% Buffer qs C) Other dosage forms Suppositories Active substances 0.0003-50% Suppository base 1-99.9% Surfactants 0-20% Lubricant 0-20% Preservatives qs

[Figure 1] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of Compound 1 obtained in Reference Example 1. [Figure 2] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of Compound 1 obtained in Reference Example 2. [Figure 3] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of Compound 1 obtained in Reference Example 3. [Figure 4] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of Compound 1 obtained in Reference Example 4. [Figure 5] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of Compound 1 obtained in Reference Example 5. [Figure 6] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of Compound 1 obtained in Reference Example 6. [Figure 7] is a diagram illustrating an X-ray diffraction pattern of the maleic acid salt of Compound 1 obtained in Reference Example 7. [Figure 8] is a diagram illustrating an X-ray diffraction pattern of the maleic acid salt of Compound 1 obtained in Reference Example 8. [Figure 9] is a diagram illustrating an X-ray diffraction pattern of the maleic acid salt of Compound 1 obtained in Reference Example 9. [Figure 10] is a diagram illustrating a TGA temperature record of the maleic acid salt of Compound 1 obtained in Reference Example 1. [Figure 11] is a diagram illustrating a TGA temperature record of the maleic acid salt of Compound 1 obtained in Reference Example 2. [Figure 12] is a diagram illustrating a TGA temperature record of the maleic acid salt of Compound 1 obtained in Reference Example 3. [Figure 13] A diagram illustrating the TGA temperature profile of the maleic acid salt of Compound 1 obtained in Reference Example 4. [Figure 14] A diagram illustrating the TGA temperature profile of the maleic acid salt of Compound 1 obtained in Reference Example 5. [Figure 15] A diagram illustrating the TGA temperature profile of the maleic acid salt of Compound 1 obtained in Reference Example 6. [Figure 16] A diagram illustrating the TGA temperature profile of the maleic acid salt of Compound 1 obtained in Reference Example 7. [Figure 17] A diagram illustrating the TGA temperature profile of the maleic acid salt of Compound 1 obtained in Reference Example 8. [Figure 18] A diagram illustrating the X-ray diffraction pattern of Compound 1 hydrochloride form A. [Figure 19] Graph showing the infrared spectrum of Compound 1 hydrochloride form A. [Figure 20] Graph showing the Raman spectrum of Compound 1 hydrochloride form A. [Figure 21] Graph showing the DSC curve of Compound 1 hydrochloride form A. [Figure 22] Graph showing the TGA temperature graph of Compound 1 hydrochloride form A. [Figure 23] Graph showing the X-ray diffraction graph of Compound 1 free base form A. [Figure 24] Graph showing the infrared spectrum of Compound 1 free base form A. [Figure 25] Graph showing the Raman spectrum of Compound 1 free base form A. [Figure 26] Graph showing the DSC curve of Compound 1 free base form A. [Figure 27] Graph showing the TGA thermogram of compound 1 free base form A. [Figure 28] Graph showing the X-ray diffraction pattern of compound 1 free base form B. [Figure 29] Graph showing the infrared spectrum of compound 1 free base form B. [Figure 30] Graph showing the Raman spectrum of compound 1 free base form B. [Figure 31] Graph showing the DSC curve of compound 1 free base form B. [Figure 32] Graph showing the X-ray diffraction pattern of compound 1 free base form C. [Figure 33] Graph showing the DSC curve of compound 1 free base form C. [Figure 34] Graph showing the TGA thermogram of compound 1 free base form C. [Figure 35] Graph illustrating the X-ray diffraction pattern of the free base form D of compound 1. [Figure 36] Graph illustrating the infrared spectrum of the free base form D of compound 1. [Figure 37] Graph illustrating the Raman spectrum of the free base form D of compound 1. [Figure 38] Graph illustrating the DSC recording curve of the free base form D of compound 1. [Figure 39] Graph illustrating the TGA temperature recording pattern of the free base form D of compound 1. [Figure 40] Graph illustrating the X-ray diffraction pattern of the free base of compound 1 obtained in Reference Example 10. [Figure 41] Graph illustrating the X-ray diffraction pattern of the free base of compound 1 obtained in Example 3.

Claims (38)

A 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride. The salt of claim 1, wherein the salt is in crystalline form. The salt of any one of claims 1 to 2, comprising 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A, characterized by one or more of the following solid state analytical properties: a. the presence of characteristic XRPD peaks at 9.2, 12.5, 14.5, 15.1, 15.8 and 17.4° 2θ (±0.2°) measured at CuKα wavelength, and/or b. the presence of characteristic XRPD peaks at 1549, 1344, 1303, 1257 and 747 cm ⁻¹ ±4 cm in its Raman spectrum. ^-1 , and/or c, characteristic absorption bands existing in the value range of 2474, 2524, 1668, 1479 and 1222 cm ^-1 (±4 cm ^-1 ) in its infrared spectrum. A salt as claimed in any one of claims 1 to 3, comprising 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A, having an XRPD pattern measured at a CuKα wavelength substantially similar to the XRPD pattern of Figure 18. The salt of any one of claims 1 to 4, wherein the salt comprises at least 5% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A. The salt of any one of claims 1 to 5, wherein the salt comprises at least 20% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A. The salt of any one of claims 1 to 6, wherein the salt comprises at least 60% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A. The salt of any one of claims 1 to 7, wherein the salt comprises at least 80% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A. The salt of any one of claims 1 to 8, wherein the salt comprises at least 95% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A. A crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A characterized by one or more of the following solid state analytical properties: a. the presence of characteristic XRPD peaks at 5.9, 17.7, 18.1, 19.8 and 22.2° 2θ (±0.2°) measured at CuKα wavelength, and/or b. the presence of characteristic XRPD peaks at 1554, 1345, 1267, 1260 and 750 cm ^-1 ±4 cm-1 in its Raman spectrum. ^-1 , and/or c, characteristic absorption bands existing in the value range of 1663, 1478, 1220, 860, 795 and 766 cm ^-1 ±4 cm ^-1 in its infrared spectrum. As for the crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of claim 10, it has an XRPD pattern measured at CuKα wavelength that is substantially similar to the XRPD pattern of Figure 23. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 5% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of any one of claims 10 to 11. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 20% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of any one of claims 10 to 12. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 60% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of any one of claims 10 to 13. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 80% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of any one of claims 10 to 14. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 95% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of any one of claims 10 to 15. A crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D characterized by one or more of the following solid state analytical properties: a. the presence of characteristic XRPD peaks at 8.1, 18.4, 18.8, 19.0 and 20.4° 2θ (±0.2°) measured at CuKα wavelength, and/or b. the presence of characteristic XRPD peaks at 1644, 1552, 1539, 1301, 1257 cm ^-1 ±4 cm -1 in its Raman spectrum. ^-1 , and/or c, characteristic absorption bands existing in the value range of 3515, 3243, 2869, 2829 and 1650 cm ^-1 ±4 cm ^-1 in its infrared spectrum. As for the crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D of claim 17, it has an XRPD pattern measured at CuKα wavelength that is substantially similar to the XRPD pattern of Figure 35. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 5% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D of any one of claims 17 to 18. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 20% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D of any one of claims 17 to 18. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 60% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D of any one of claims 17 to 19. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 80% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D of any one of claims 17 to 20. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 95% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D of any one of claims 17 to 21. A pharmaceutical composition comprising a solid form of the hydrochloride or free base of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one as claimed in claims 1 to 23 and a pharmaceutically acceptable carrier. A method for preparing a salt as claimed in any one of claims 1 to 9, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) mixing the solution in step a) with HCl solution c) stirring the slurry; and d) 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride monohydrate, Wherein, the solvent used in steps a) and b) is selected from the group consisting of: water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a salt as claimed in any one of claims 1 to 9, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt in any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; and c) agitating the slurry; and d) Monoisocyanate 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt form A, Wherein, the solvent used in step a) is selected from the group consisting of: water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a salt as claimed in any one of claims 1 to 9, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt in any suitable solvent; b) cooling the solution to obtain a slurry; and c) agitating the slurry; and d) Monoisocyanate 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt form A, Wherein, the solvent used in step a) is selected from the group consisting of: water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a salt as claimed in any one of claims 1 to 9, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt in any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) agitating the slurry; and d) Monoisocyanate 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt form A, The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base form A polymorph as in any one of claims 10 to 16, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, Wherein, the solvent used in step a) is selected from the group consisting of: water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base form A polymorph as in any one of claims 10 to 16, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) cooling the solution to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, Wherein, the solvent used in step a) is selected from the group consisting of: water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base form A polymorph as in any one of claims 10 to 16, comprising: a) providing a suspension of the solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) stirring the slurry; and c) monoisocyanate 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, Wherein, the solvent used in step a) is selected from the group consisting of: water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base form A polymorph as in any one of claims 10 to 16, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) mixing the solution with an antisolvent to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tertiary butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tertiary butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, tertiary butyl methyl ether or a mixture thereof. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base form D polymorph as in any one of claims 17 to 23, comprising: a) providing a solution of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) stirring the slurry; and d) mono-4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, wherein the solvent used in step a) is selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, acetone, butanone, 2-pentanone, 3-pentanone, acetonitrile, tetrahydrofuran, 2-methoxyethanol, or a mixture thereof. A solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one or its hydrochloride as claimed in claims 1 to 23, which is used to treat/prevent diseases or conditions related to melanin-concentrating hormone receptor 1 activity. The solid form of claim 34, wherein the disease or condition associated with melanin-concentrating hormone receptor 1 activity is selected from the group consisting of obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and Prader-Willi syndrome. The solid form of claim 35, wherein the disease or condition associated with melanin-concentrating hormone receptor 1 activity is Prader-Willi syndrome. The solid form of claim 36, wherein the use provides improvement in one or more symptoms of Prader-Willi syndrome. The solid form of claim 37, wherein one or more symptoms of Prader-Willi syndrome is binge eating disorder.

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